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Are cannabidiol and Δ(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review.
Br J Pharmacol 2015; 172(3):737-53BJ

Abstract

Based upon evidence that the therapeutic properties of Cannabis preparations are not solely dependent upon the presence of Δ(9) -tetrahydrocannabinol (THC), pharmacological studies have been recently carried out with other plant cannabinoids (phytocannabinoids), particularly cannabidiol (CBD) and Δ(9) -tetrahydrocannabivarin (THCV). Results from some of these studies have fostered the view that CBD and THCV modulate the effects of THC via direct blockade of cannabinoid CB1 receptors, thus behaving like first-generation CB1 receptor inverse agonists, such as rimonabant. Here, we review in vitro and ex vivo mechanistic studies of CBD and THCV, and synthesize data from these studies in a meta-analysis. Synthesized data regarding mechanisms are then used to interpret results from recent pre-clinical animal studies and clinical trials. The evidence indicates that CBD and THCV are not rimonabant-like in their action and thus appear very unlikely to produce unwanted CNS effects. They exhibit markedly disparate pharmacological profiles particularly at CB1 receptors: CBD is a very low-affinity CB1 ligand that can nevertheless affect CB1 receptor activity in vivo in an indirect manner, while THCV is a high-affinity CB1 receptor ligand and potent antagonist in vitro and yet only occasionally produces effects in vivo resulting from CB1 receptor antagonism. THCV has also high affinity for CB2 receptors and signals as a partial agonist, differing from both CBD and rimonabant. These cannabinoids illustrate how in vitro mechanistic studies do not always predict in vivo pharmacology and underlie the necessity of testing compounds in vivo before drawing any conclusion on their functional activity at a given target.

Authors+Show Affiliations

Division of Molecular Biology, GW Pharmaceuticals, Salisbury, Wiltshire, UK.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Review
Systematic Review

Language

eng

PubMed ID

25257544

Citation

McPartland, John M., et al. "Are Cannabidiol and Δ(9) -tetrahydrocannabivarin Negative Modulators of the Endocannabinoid System? a Systematic Review." British Journal of Pharmacology, vol. 172, no. 3, 2015, pp. 737-53.
McPartland JM, Duncan M, Di Marzo V, et al. Are cannabidiol and Δ(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172(3):737-53.
McPartland, J. M., Duncan, M., Di Marzo, V., & Pertwee, R. G. (2015). Are cannabidiol and Δ(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. British Journal of Pharmacology, 172(3), pp. 737-53. doi:10.1111/bph.12944.
McPartland JM, et al. Are Cannabidiol and Δ(9) -tetrahydrocannabivarin Negative Modulators of the Endocannabinoid System? a Systematic Review. Br J Pharmacol. 2015;172(3):737-53. PubMed PMID: 25257544.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Are cannabidiol and Δ(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. AU - McPartland,John M, AU - Duncan,Marnie, AU - Di Marzo,Vincenzo, AU - Pertwee,Roger G, PY - 2014/02/21/received PY - 2014/09/12/revised PY - 2014/09/16/accepted PY - 2014/9/27/entrez PY - 2014/9/27/pubmed PY - 2015/11/3/medline SP - 737 EP - 53 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 172 IS - 3 N2 - Based upon evidence that the therapeutic properties of Cannabis preparations are not solely dependent upon the presence of Δ(9) -tetrahydrocannabinol (THC), pharmacological studies have been recently carried out with other plant cannabinoids (phytocannabinoids), particularly cannabidiol (CBD) and Δ(9) -tetrahydrocannabivarin (THCV). Results from some of these studies have fostered the view that CBD and THCV modulate the effects of THC via direct blockade of cannabinoid CB1 receptors, thus behaving like first-generation CB1 receptor inverse agonists, such as rimonabant. Here, we review in vitro and ex vivo mechanistic studies of CBD and THCV, and synthesize data from these studies in a meta-analysis. Synthesized data regarding mechanisms are then used to interpret results from recent pre-clinical animal studies and clinical trials. The evidence indicates that CBD and THCV are not rimonabant-like in their action and thus appear very unlikely to produce unwanted CNS effects. They exhibit markedly disparate pharmacological profiles particularly at CB1 receptors: CBD is a very low-affinity CB1 ligand that can nevertheless affect CB1 receptor activity in vivo in an indirect manner, while THCV is a high-affinity CB1 receptor ligand and potent antagonist in vitro and yet only occasionally produces effects in vivo resulting from CB1 receptor antagonism. THCV has also high affinity for CB2 receptors and signals as a partial agonist, differing from both CBD and rimonabant. These cannabinoids illustrate how in vitro mechanistic studies do not always predict in vivo pharmacology and underlie the necessity of testing compounds in vivo before drawing any conclusion on their functional activity at a given target. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/25257544/Are_cannabidiol_and_Δ_9___tetrahydrocannabivarin_negative_modulators_of_the_endocannabinoid_system_A_systematic_review_ L2 - https://doi.org/10.1111/bph.12944 DB - PRIME DP - Unbound Medicine ER -